The treatment of pain is a critical health issue. Acute (e.g., postoperative pain) and chronic (e.g., arthritis, low back, cancer) pain affects tens of millions of people annually in the US. Each year some 30 million people visit a physician with a complaint of a painful condition. Some 10% of these patients are seen with chronic pain as their main complaint. The financial loss due to pain has been estimated to exceed 100 billion dollars a year as a result of medical fees, decreased productivity, litigation and the cost of drugs. New therapeutic agents with broader efficacy, for nociceptive, neuropathic and mixed nociceptive-neuropathic pain syndromes, and with fewer side effects would result in significant societal benefit.
Pain can be broadly divided into two categories: nociceptive and neuropathic pain. Nociceptive pain occurs as a result of activation of peripheral nociceptors, actually free nerve endings by noxious stimuli (heat, pressure, inflammatory mediators). Examples of nociceptive pain include postsurgical pain, inflammatory pain (e.g., arthritis) and low back pain. Such a pain is often described as “a constant, dull, aching pain”. Neuropathic pain occurs as a result of damage to the peripheral or central nervous system. Examples of neuropathic pain include radiculopathy (e.g., disc impingement on a nerve), complex regional pain syndrome (CRPS I, II), diabetic peripheral neuropathy or central pain (stroke, spinal cord injury, multiple sclerosis). Patients typically describe neuropathic pain as “burning and tingling” in nature. It is characterized by hyperalgesia (increased painful response to a noxious stimulus) and allodynia (pain to a previously non-noxious stimulus).
In many pain patients, in particular those with chronic pain conditions of both malignant (cancer-related pain) and non-malignant origin, pain is inadequately managed with currently available drugs. Available drugs are simple modifications (e.g., extended release) of drugs from classes which have been available for decades including the opioids, nonsteroidal anti-inflammatory agents (NSAID's) or various adjuvants (antidepressants, anticonvulsants) initially approved for other uses besides pain. Opioids (e.g., morphine, oxycodone) are often successfully used for the treatment of moderate to severe nociceptive pain. Chronic neuropathic pain is much less responsive to opioids. Use of opioid analgesics is associated with a broad range of significant side effects including cognitive impairment, respiratory depression and constipation. In addition, long-term opioid dosing results in the development of tolerance to the analgesic effect, drug abuse and dependence. The NSAID's (e.g., ibuprofen) act by inhibition of the cyclo-oxygenase (Cox-1,2) enzyme. They are especially useful in nociceptive pain of inflammatory origin (e.g., arthritis). However, the NSAID's have limited efficacy when compared to the opioids. In addition, NSAID's have significant side effects (renal, gastrointestinal, cardiovascular). The discovery of the Cox-2 selective agents (e.g., rofecoxib-Vioxx®; celecoxib-Celebrex®; valdecoxib-Bextra®) which have far less gastrointestinal toxicity, was thought to be an advance in NSAID pharmacology. Nonetheless, these agents still have low efficacy and evidence is now available linking them to significant cardiovascular events including stroke and myocardial infarction following chronic use. This has resulted in the removal of both rofecoxib and valdecoxib from the market. No truly efficacious agent exists for the treatment of neuropathic pain. GABA-pentin (Neurontin®), an anticonvulsant, has found use for some neuropathic pain syndromes (e.g., diabetic peripheral neuropathy, postherpetic neuralgia), but it still has limited efficacy. Duloxetine (Cymbalta®), an antidepressant, has recently been approved for the treatment of diabetic peripheral neuropathy. However, it has limited efficacy and usefulness for other neuropathic pain states. The N-methyl-d-aspartate (NMDA) receptor antagonists (e.g., ketamine) have been proposed for the treatment of neuropathic pain. Their general use is impractical given the marked side effects including sedation, psychosis and motor impairment. The limitations of the currently available therapies clearly demonstrate the need for a broad spectrum new class of efficacious and safe analgesic drugs for the treatment of nociceptive and neuropathic pain.
Given the need for more effective, less toxic, analgesic drugs, a great deal of emphasis has been placed on identifying novel molecular targets that could form the basis for new analgesics. One of the promising new targets is the neuronal nicotinic acetylcholine receptor (nAChR). nACHR's play an important role in the control of pain and thus drugs acting at the nicotinic receptor, as agonists, partial agonists or antagonists may be expected to have analgesic properties. The bis-quaternary ammonia salts of the invention are thought to interact with the nACHR. Nicotinic receptor drugs have been shown to have a broad spectrum of analgesic activity in several preclinical models of pain of nociceptive and neuropathic origin. This includes acute thermal pain models (tail flick, hot plate), inflammatory pain models (formalin or carrageenan injection into the paw) and nerve injury (neuropathic pain) models (spinal or sciatic nerve ligation). Both anti-hyperalgesic and anti-allodynic effects were observed in the neuropathic pain models.
Thus, it appears that nicotine drugs have promise as analgesic agents for the treatment of several types of clinical pain, specifically nociceptive, neuropathic and inflammatory pain.